Epidermal growth factor receptor (EGFR) signaling is fundamentally important for tissue homeostasis through EGFR/ligand interactions that stimulate numerous signal transduction pathways. Aberrant EGFR signaling has been reported in inflammatory and malignant diseases but thus far no primary inherited defects in EGFR have been recorded. Using whole-exome sequencing, we identified a homozygous loss-of-function missense mutation in EGFR (c.1283G>A; p.Gly428Asp) in a male infant with life-long inflammation affecting the skin, bowel and lungs. During the first year of life, his skin showed erosions, dry scale, and alopecia. Subsequently, there were numerous papules and pustules – similar to the rash seen in patients receiving EGFR inhibitor drugs. Skin biopsy demonstrated an altered cellular distribution of EGFR in the epidermis with reduced cell membrane labeling, and in vitro analysis of the mutant receptor revealed abrogated EGFR phosphorylation and EGF-stimulated downstream signaling. Microarray analysis on the patient’s skin highlighted disturbed differentiation/premature terminal differentiation of keratinocytes and upregulation of several inflammatory/innate immune response networks. The boy died aged 2.5 years from extensive skin and chest infections as well as electrolyte imbalance. This case highlights the major mechanism of epithelial dysfunction following EGFR signaling ablation and illustrates the broader impact of EGFR inhibition on other tissues.

Background The WHO's Vision 2020 global initiative against blindness, launched in 2000, prioritises children. Progress has been hampered by the global paucity of epidemiological data about childhood visual disability. The British Childhood Visual Impairment and Blindness Study 2 (BCVIS2) was undertaken to address this evidence gap. Methods UK-wide prospective population-based observational study of all those aged under 18 years newly diagnosed with visual impairment or blindness between Oct 1, 2015 and Nov 1 2016. Eligible children were notified simultaneously but independently by their managing ophthalmologists and paediatricians via the two national active surveillance schemes, the British Ophthalmic and Paediatric Surveillance Units. Standardised detailed data were collected at diagnosis and one year later. Incidence estimates and relative rates by key sociodemographic factors were calculated. Descriptive analyses were undertaken of underlying ophthalmic disorders and nonophthalmic comorbidities. FindingsOf 784 cases, 72% had additional non-ophthalmic impairments/disorders and 4% died within the year. Annual incidence was highest in the first year of life, 5•2 per 10,000 (95% CI 4•7-5•7) with cumulative incidence by 18 years of 10•0 per 10,000 (95% CI 9•4 to 10•8). Rates were higher for those from any ethnic minority group, the lowest quintile of socio-economic status, born preterm or with low birthweight. Only 44% had a single ophthalmic condition: disorders of the brain/visual pathways affected 48% overall. Prenatal or perinatal aetiological factors accounted for 84% of all conditions. InterpretationBCVIS2 provides a contemporary snapshot of the heterogeneity, multi-morbidity and vulnerability associated with childhood visual disability in a high income country, and the arising complex needs. These findings will facilitate developing and delivering healthcare and planning interventional research. They highlight the importance of including childhood visual disability as a sentinel event and metric in global child health initiatives.

We have studied the effect of intravenous epinephrine, albuterol, verapamil, and aminophylline on airway microvascular leakage in guinea pigs. Microvascular leakage was induced by platelet-activating factor (PAF; 50 ng/kg intravenously), which acts directly on venular endothelial cells, and measured by quantifying extravasation of Evans blue (EB) dye. Epinephrine (20 micrograms/kg) inhibited PAF-induced changes in dye leakage in larynx and main bronchi; at 80 and 160 micrograms/kg, significant inhibition was observed in all airways studied. This effect was reversed by phentolamine (2.5 mg/kg) or prazosin (100 micrograms/kg). By contrast, albuterol (20 to 320 micrograms/kg) and aminophylline (12.5 to 50 mg/kg) failed to inhibit dye leakage at any dose studied. Verapamil inhibited PAF-increased leakage in larynx, main bronchi, and intrapulmonary airways at the lowest dose tested (125 micrograms/kg), although inhibition was not dose dependent. These results suggest that the antiedema effect of epinephrine may be due to vasoconstriction rather than to a direct effect on endothelial cell contractility and that neither beta-agonists nor theophylline have an inhibitory effect. The inhibitory effect of epinephrine on airway microvascular leakage may have therapeutic implications for asthma.

5 These results show that combined inhibition of the type 3 and 4 PDE isoenzymes in HPBM from normal subjects has a greater antiproliferative effect than inhibition of the type 4 isoenzyme alone. In addition these data indicate that the proliferative response of HPBM from AD subjects is more sensitive to PDE 4 inhibition than the proliferation of HPBM from normals.

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Osteopoikilosis is an uncommon cause of multiple osteosclerotic bone lesions. The skeletal changes of osteopoikilosis (synonyms: osteopathia condensans disseminata, spotted bone) were first described by Stieda in 1905 and subsequently by Albers-Schoenberg (1915). Radiologically, the lesions consist of multiple wellcircumscribed round or oval opacities, each 1–10 mm in diameter. The mottling is more marked in the epiphyses and metaphyses of the long bones and the pelvis, but is also common in the spongiosa of the phalanges, carpal and tarsal bones. The changes are more common in men than women and usually present in adulthood, although osteopoikilosis has been reported in children. Familial aggregation has been described, and autosomal dominant inheritance with variable expression is proposed (Schoenenberg, 1975). Osteopoikilosis should be considered in the differential diagnosis of multiple osteosclerotic bone lesions, but is a relatively uncommon finding. Serowy (1956) could find only 100 reported cases in the literature over a 25-year period since its initial description, and Jonasch (1955) found only 12 cases of osteopoikilosis in a series of 21000 radiographs.

Langerhans cells (LCs) subserve an important antigen-presenting function in the skin immune system. They bear CD4 receptors, which make them potential targets for infection with the human immunodeficiency virus (HIV-1). The observation of reduced numbers of LCs in the skin of patients with the acquired immunodeficiency syndrome (AIDS), and the association of severe psoriasis with HIV-1 infection, raise interesting questions regarding the role of LCs in the skin of HIV-1-positive psoriatic patients. In this study, LCs were quantified in the lesional and non-lesional skin of seven HIV-1-positive psoriatic patients, and the results were compared with age-, sex- and site-matched HIV-1-negative psoriatic patients. The number of LCs was determined by staining skin sections with S-100 polyclonal antibody, using the three-step avidin-biotin immunoperoxidase method. The S-100-positive cells above the basal layer were quantified in two ways: cells/mm2 of epidermal area, and cells/mm of length of basement membrane. HIV-1-positive psoriatic patients showed a reduction in the number of epidermal LCs compared with HIV-1-negative psoriatic patients using both methods of quantification, in both lesional and non-lesional skin (P < 0.05, Mann-Whitney test). In addition, a reduction in the number of LCs in lesional compared with non-lesional skin was observed in both HIV-1-positive and -negative patients when LCs were quantified per mm2 of epidermal area (P < 0.05, Wilcoxon test).(ABSTRACT TRUNCATED AT 250 WORDS)